0094 Hypnotic Effectiveness Of The Dual Orexin Receptor Antagonist DORA-22, Evaluated With A Rodent Cage-Change Model Of Insomnia. (27th April 2018)

• Record Type: Journal Article
• Authors: McKenna, J T; Gamble, M C; Anderson-Chernishof, M B; McCoy, J G; Strecker, R E
• Is Part Of: Sleep. Volume 41(2018)Supplement 1
• Page Start: A38
• Page End: A38
• Publication Date: 2018-04-27
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsy061.093
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Insomnia involves disruption of sleep initiation, maintenance, and/or overall quality, and impairs cognition. Of utmost importance is the development of hypnotics that improve the sleep profile of the insomniac, but minimally impair cognition. We previously established a rodent cage change insomnia model, which produced sleep disruption and associated sleep dependent memory consolidation (SDMC) impairment, assessed as performance on a spatial reference memory version of the Morris Water Maze (MWM). We evaluated if treatment with the dual orexin receptor antagonist DORA-22 would improve insomnia model-induced sleep disruption and MWM performance deficits. Methods: Rats were trained to remember platform location in MWM (Acquisition), and then administered (gavage) vehicle (20% TPGS) or DORA-22 (either 10, 30, or 100 mg/kg dose, Merck and Co., Inc.). Animals were then exposed to 6 hrs of a double-dirty cage change-induced insomnia model (DDCI, rat placed into a dirtied cage, and another 3 hrs later). Memory for platform location was then evaluated by a probe trial. Results: Non-repeated ANOVA analysis revealed a significant difference between treatments at doses of 10, 30, and 100 mg/kg, compared to vehicle, for pooled (6 hr) amounts of wake (P=0.015) and NREM sleep (P=0.029). NREM sleep latencies (first full bout ≥1 min following gavage treatment) also significantly differed (P=0.001). Water maze measures indicated a trend of improved performance due to DORA-22 treatment. Compared to vehicle, 10 mg/kg produced a 29.1% increase of time spent in target quadrant (Student's t, one-tailed independent samples; P<0.04), 89.8% increase of platform location entry number (P<0.02), and 27.0% increase (P<0.05) of % of total distance swam in target quadrant. Conclusion: Our DDCI model disrupted sleep and attenuated SDMC. DORA-22 treatment was hypnotically effective, with notable improvement of DDCI-induced sleep disruption and associated SDMC deficits. Support (If Any): Merck MISP (PI McKenna); salary support for RES from VA Merit I01 BX002774.